1. Field of the Invention
The present invention relates generally to methods for lowering intracellular free calcium levels, and more particularly to methods and pharmaceutical compositions for lowering intracellular free calcium levels in mammalian hosts.
Elevated intracellular free calcium levels are associated with a number of pathogenic conditions, such as muscular dystrophy, hypertension, traumatic brain injury, stroke, Alzheimer's disease, and the like. It would be desirable to identify active compounds, pharmaceutical compositions, and methods which are capable of lowering intracellular free calcium levels and at least partially alleviating such conditions.
2. Description of the Background Art
Dystrophic conditions in mouse muscle fibers have been associated with elevated free intracellular calcium levels (Turner et al. (1988) Nature 335:735-738), and such elevated calcium levels have been associated with enhanced calcium influx through calcium (Ca.sup.+2) leak channels (Fong et al. (1990) Science 250:673-676). Coulombe et al. (1989) J. Membr. Biol. 111:57-67, reported that compound Bay K 8644 increased activity in cardiac calcium leak channels. Turner et al. (1991) J. Cell Biol. 115:1701-1712, reported that nifedipine (4-(2'-nitrophenyl-2,6-dimethyl-3,5-dicarboxymethyloxy-1,4-dihydropyridine ) increases calcium leak channel activity and intracellular free calcium in dystrophic mouse (mdx) skeletal muscle fibers and myotubes and human Duchenne muscular dystrophy myotubes, and predicted that any agent that would significantly reduce leak channel activity will result in lowered free intracellular calcium concentrations. Compound Bay K 8644 and nifedipine are both dihydropyridine compounds. Dihydropyridines are known to modulate the activity of L-channels, a class of calcium channels distinct from leak channels.
U.S. Pat. No. 4,771,057 and Guengerich et al. (1991) J. Med. Chem. 34:1838-1844, describe the preparation of various dihydropyridine derivatives, including 4-(3'-trifluoromethylphenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydropy ridine.
The full disclosures of each of these background references are incorporated herein by reference.